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‘Estrogen Module’ Predicts If Breast Cancer Patients Should Have 10 vs. 5 Years of Hormone Therapy

GLASGOW, SCOTLAND—A subset of genomic biomarkers associated with hormone dependency—called the estrogen (E) module—could be used to predict which women with ER-positive HER2-negative breast cancer could benefit from 10 years of endocrine therapy rather than five, according to findings reported here at the European Breast Cancer Conference (Abstract 216).

“When we looked at the women with HER2-negative breast cancer and defined them according to their E-module score, which indicated how sensitive to estrogen their tumors were, we found there was a striking difference,” said Mitch Dowsett, PhD, Professor of Biochemical Endocrinology and Head of both the Academic Department of Biochemistry and the Centre for Molecular Pathology at the Institute of Cancer Research and the Royal Marsden Hospital and Head of Biochemistry at the Royal Marsden NHS Foundation Trust in London, speaking at a news briefing.

“We found that patients with the highest estrogen receptor positivity in their tumors—as measured by messenger RNA—show a ‘step up’ in their recurrence rate at the end of five years when they cease their treatment,” he noted.

Women whose tumors were negative for human epidermal growth factor protein HER2 but very sensitive to estrogen more than doubled their risk of recurrence between five and 10 years after surgery—from 5.7 percent in the first five years to 13.6 percent in the next five years—unless adjuvant hormone therapy was extended.

This was in contrast to women who had low E-module scores, in whom there was little difference in recurrence rates between the first and next five years: 10.3 vs. 12.3 percent.

His team collaborated with researchers at the Wolfson Institute of Preventive Medicine, Queen Mary University of London, led by Jack Cuzick, PhD, Professor of Epidemiology.

The study extracted data from the OncotypeDx 21-gene recurrence score from 1,125 postmenopausal women with ER-positive breast cancer from the ATAC trial, 90 percent of whom were HER2-negative. In an average of 10 years of follow-up there were 215 recurrences.

“We've been looking at the molecular features of these tumors and have discerned a somewhat surprising result,” Dowsett said in an interview after his talk. He explained that although the OncotypeDx test is usually reported as a single score, it is made up of 16 “informative” genes and five control or “housekeeper” genes. But some of the 16 genes can be considered as groups rather than as individuals: “One of these is the E module, which consists of four genes related to estrogen signaling, including the estrogen receptor itself.”

He pointed out that predictive molecular tests were already being used to make decisions about adding cytotoxic chemotherapy, and that this could now be a way to apply a genomic tool to predict benefit from hormone therapy beyond five years.

“We are already testing over 900 tumors from the ATAC trial to see if we can identify the estrogen-sensitive tumors better than by the genes in the Oncotype test,” Dowsett said.

‘Level of Expression Is Important’

Also in an interview, Cuzick that it had long been known that women with ER-positive cancers had higher late recurrence rates than those with ER-negative tumors, and he said the new research showed that even within ER+ cancers the level of expression is important.

He said his group is now looking at the use of extended therapy with aromatase inhibitors in patients who have ER+ breast cancer with other unfavorable characteristics, and at using other drugs with the potential to prevent breast cancer recurrence, including bisphosphonates and metformin.

“Hopefully this biomarker work will help to pinpoint more accurately which patients need additional treatment,” he said.

Dowsett concluded: “It is commonly thought that the reduction in recurrence achieved by five years of endocrine therapy carries over into the next five years. Our results suggest this effect may differ markedly between different groups of ER+ tumors. We need to do more detailed analyses on large numbers of tumors to find out if this is the case.”